CN1282743A - New beta-carbiline compounds, their preparation method and medicine composition conterning same - Google Patents
New beta-carbiline compounds, their preparation method and medicine composition conterning same Download PDFInfo
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- CN1282743A CN1282743A CN00121615A CN00121615A CN1282743A CN 1282743 A CN1282743 A CN 1282743A CN 00121615 A CN00121615 A CN 00121615A CN 00121615 A CN00121615 A CN 00121615A CN 1282743 A CN1282743 A CN 1282743A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
A compound selected from those of formula (I): wherein: dotted line represents single or double bond, R1 represents hydrogen, alkyl, -R6-aryl, -R6-cycloalkyl, -R6-heterocycle, -CO2R7-, -COR8, or -CONHR8, wherein R6, R7, and R8 are as defined in the description, R2 represents cyano, mono- or di-alkylaminoalkylaminocarbonyl, -CO2R8, -CONHR8, -NR8R9, -NHCO2R7, or -COR8 wherein R7, R8, and R9 are as defined in the description,R3 and R4 together form (C3-C10)cycloalkyl,R5 represents hydrogen, alkyl, or arylalkyl, Ra, Rb, Rc, Rd, which may be identical or different, represent a group as defined in the description, its isomers, and pharmaceutically-acceptable acid or base addition salts thereof.
Description
The present invention relates to novel 'Beta '-carboline compound, their preparation method and contain their pharmaceutical composition.This new compound is to 5-HT
2Receptoroid has the serotonergic activity.
Thrombotonin is a kind of not only by the maincenter mode but also act on the neurotransmitter of 5-HT (serotonin) acceptor by the periphery mode.Identify 14 kinds of serotonin receptor hypotypes so far, be divided into 5-HT
1To 5-HT
7Seven classes.At 5-HT
2In the class, 5-HT
2A, 5-HT
2BAnd 5-HT
2CHypotype is known.These hypotypes have similar action (" pharmacology science trend " 1995,16,105-110 on the specificity to a large amount of parts; " neuropharmacology " 1994,33,275-317).
Because some compound can be regulated 5-HT
2Acceptor, especially 5-HT
2CAnd 5-HT
2BThe activity of acceptor, they are applicable to for example following treatment of diseases: somnopathy (" psychopharmacology " 1989,97,436-442; " neuropharmacology " 1994,33,467-471), appetite disorder (" psychopharmacology " 1997,133,309-312), panic attack, phobia, anxiety (" Britain's pharmacology magazine " 1996,117,427-434; " neuropharmacology " 1997,36,793-802), depressed (" biological psychiatry " 1996,39,1000-1008; " neuroscience " 1999,91 (2), 587-597), impulsion property and (" pharmacy, the biochemical and behavior " 1991,39 of aggressiveness illness, 729-736), sexual dysfunction (" clinical neuropharmacology " 1997,20 (3), 210-214), migraine (" drug research progress " 1998,51,219-244, Springer Verlay), schizophrenia and psychosis (" European pharmacology magazine " 1993,245,179-182; " biological psychiatry " 1998,44,1099-1117).
A large amount of 'Beta '-carboline compounds have been described in the document.Especially see European patent application EP 0620223, its claimed Tetrahydropyridoindoderivatives compound, these compounds are to 5-HT
2CAcceptor has the intensive affinity.The claimed 'Beta '-carboline compound of European patent application EP 0320079 and EP0300541, i.e. dihydro-β-Ka Lin and tetrahydrochysene-β-Ka Lin, they have intensive scleroproein degrading activity.At last, International Patent Application WO 95/24200 has been described the compound with specific tetrahydrochysene-β-Ka Lin structural pattern.These compounds are 5-HT
2BThe specific antagonists of acceptor.
Except The compounds of this invention was novel, they also were proved to be effective 5-HT
2The selective ligands of acceptor, particularly 5-HT
2CAnd 5-HT
2BAntagonist, so they can be used for depression, psychosis, schizophrenia, phobia, anxiety, panic attack, somnopathy, appetite disorder, impulsion and aggressiveness illness, sexual dysfunction and migrainous treatment.
The present invention more properly relates to the formula I compound:
Wherein:
Represent a singly-bound or two key, randomly can give carry them ring with aromatic character,
R
1The group of representative is selected from:
◆ hydrogen,
◆ straight or branched (C
1-C
6) alkyl,
◆-R
6-aryl ,-R
6-cycloalkyl ,-R
6-heterocycle, wherein R
6Base is represented straight or branched (C
1-C
6) alkylidene group,
◆-CO
2R
7, R wherein
7Represent straight or branched (C
1-C
6) alkyl, aryl, cycloalkyl, heterocycle ,-R
6-aryl ,-R
6-cycloalkyl or-R
6-heterocycle, wherein R
6Be as defined above,
◆-COR
8, R wherein
8Represent hydrogen atom, straight or branched (C
1-C
6) alkyl, aryl, cycloalkyl, heterocycle ,-R
6-aryl ,-R
6-cycloalkyl or-R
6-heterocycle, wherein R
6Be as defined above,
◆-CONH-R
8, R wherein
8Be as defined above,
Perhaps ought carry R
1Nitrogen-atoms when having carried cyclic olefinic bond, R
1Do not exist,
R
2The group of representative is selected from:
◆ cyano group,
◆-CO
2R
8, R wherein
8Be as defined above,
◆-CONHR
8, R wherein
8Be as defined above,
◆ single (C
1-C
6) alkylamino (C
1-C
6) alkyl amino-carbonyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl amino-carbonyl, the moieties of each group can be a straight or branched,
◆-NR
8R
9, R wherein
8Be as defined above, R
9Representative is as R
8Defined group,
◆-NH-CO
2R
7, R wherein
7Be as defined above,
◆-COR
8, R wherein
8Be as defined above,
R
3And R
4Form (C together
3-C
10) cycloalkyl,
R
5Represent hydrogen atom, straight or branched (C
1-C
6) alkyl or aryl-(C
1-C
6) alkyl, the latter's moieties can be a straight or branched,
Ra, Rb, Rc and Rd can be identical or different, and the group of representative is selected from hydrogen, halogen, straight or branched (C independently of one another
1-C
6) alkyl, hydroxyl, straight or branched (C
1-C
6) alkoxyl group, straight or branched three halo (C
1-C
6) alkyl, straight or branched three halo (C
1-C
6) alkoxyl group, nitro, cyano group, amino, straight or branched (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino--wherein each moieties can be a straight or branched--, aryl, aryl-(C
1-C
6) alkyl--wherein moieties can be a straight or branched--, carboxyl, straight or branched (C
1-C
6) alkyl-carbonyl oxygen base, straight or branched (C
1-C
6) acyl group, aryloxy and aryl-(C
1-C
6) alkoxyl group--wherein the alkoxyl group part can be a straight or branched--,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali,
Self-evident:
That-" cycloalkyl " is understood that is single-or two-cyclic group, it is saturated (perhaps randomly containing the one or more degrees of unsaturation of ring system with aromatic character of can not giving), contain 3 to 10 carbon atoms, randomly replaced by one or more identical or different groups, substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl and straight or branched (C
1-C
6) alkoxyl group,
-" aryl " is understood that phenyl, naphthyl, tetralyl, dihydro naphthyl, indenyl or 2, and 3-dihydro indenyl is randomly replaced by one or more identical or different groups separately, and substituting group is selected from halogen, hydroxyl, cyano group, nitro, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, amino, straight or branched (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino--wherein each moieties can be a straight or branched--, aryloxy, aryl-(C
1-C
6) alkoxyl group--wherein alkoxyl group part can be straight or branched--, straight or branched three halo (C
1-C
6) alkyl, straight or branched (C
1-C
6) acyl group, straight or branched (C
1-C
6) alkoxy carbonyl, straight or branched (C
1-C
6) alkyl amino-carbonyl and oxo,
That-" heterocycle " is understood that is saturated or undersaturated, single-or two-cyclic group, have aromatics or non-aromatic character, have 5 to 12 annular atomses, contain one, heteroatoms that two or three are identical or different, heteroatoms is selected from oxygen, nitrogen and sulphur, heterocycle is understood that and can be randomly replaced by one or more identical or different groups that substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, nitro, oxo and amino is (optional by one or two straight or branched (C
1-C
6) the alkyl replacement).
In heterocycle, can be symbolic and do not add any pyridyl, thienyl, furyl, imidazolyl, 4H-pyrans-4-ketone, pyrazinyl, pyrimidyl, isoxazolyl, tetrazyl, pyrryl, pyrazolyl, quinolyl, isoquinolyl, quinazolyl, pyrrolidyl, piperidyl, piperazinyl, 1 restrictedly mentioned, 2, the 3-thiadiazolyl group,
In pharmaceutically acceptable acid, can not add any hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphonic acids, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, dextrocamphoric acid etc. restrictedly mentioned.
In pharmaceutically acceptable alkali, can not add any sodium hydroxide, potassium hydroxide, triethylamine, TERTIARY BUTYL AMINE etc. restrictedly mentioned.
According to a kind of favourable change example, preferably The compounds of this invention is, wherein R
3With R
4Form saturated, monocyclic (C together
3-C
10) cycloalkyl, it is randomly replaced by one or more groups as defined above.Especially advantageously, R
3With R
4Form replacement, saturated, monocyclic (C together
4-C
6) cycloalkyl.More particularly, R
3With R
4Form cyclobutyl together.
According to the present invention, preferred substituted R
1Be hydrogen atom and-COR
8Base, wherein R
8Define as formula I.According to a kind of favourable change example, preferred substituted R
1Be-COR
8aBase, wherein R
8aRepresent aryl or heterocycle.
According to the present invention, preferred substituted R
2Be-CO
2R
8Base, wherein R
8Define as formula I.According to a kind of favourable change example, preferred substituted R
2Be-CO
2R
8bBase, wherein R
8bRepresent straight or branched (C
1-C
6) alkyl or cycloalkyl.Especially advantageously, R
8bRepresent ethyl or cyclopentyl.
According to the present invention, preferred substituted R
5It is hydrogen atom.
According to a kind of especially favourable change example, preferred The compounds of this invention is 2,3,4 of a formula (I '), 9-tetrahydrochysene-1H-'Beta '-carboline compound:
Wherein:
R
1, R
2, R
3, R
4, R
5, Ra, Rb, Rc and Rd such as formula I definition.
According to the present invention, preferred compound is:
1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid ring pentyl ester,
1-(6-bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
1-[6-chloro-2-(1H-imidazoles-5-base carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate,
1-(6-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
1-(5,6-two chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
1-(6,7-two chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate and
1-(6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate.
The isomer of preferred compound and constitute the part of complete content of the present invention with pharmaceutically acceptable acid or the formed additive salt of alkali.
The invention still further relates to the preparation method of formula I compound, it is characterized in that using the formula II compound as raw material:
Wherein Ra, Rb, Rc, Rd and R
5As the formula I definition,
According to the synthesis condition that is applicable to peptide coupling type, make the reaction of this formula II compound and formula III compound:
R wherein
3And R
4As the formula I definition,
Obtain the formula IV compound:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
In the presence of phosphoryl chloride, in a kind of solvent, for example toluene or benzene are handled this formula IV compound, obtain formula (I/a) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
This formula (compound of I/a):
★ is according to the normal condition in organic synthesis reduction, obtain formula (I/b) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
Under alkaline condition, in the presence of formula (V) compound:
R
1-X (Ⅴ)
R wherein
1As the formula I definition, X represents leavings group commonly used in the organic synthesis,
To this formula (I/b) compound is handled, obtain formula (II/c) compound, i.e. the formula I compound specific examples:
★ or be subjected in the organic synthesis effect of oxygenant commonly used, obtain formula (I/d) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
All formulas (I/a), (I/b), (I/c) and (the compound constitutional formula of I/d) (I/e) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5As the formula I definition,
This formula (compound of I/e)
* in the presence of Lewis acid and formula VI compound:
R
7-OH (Ⅵ)
R wherein
7As the formula I definition,
Be subjected to transesterification, obtain formula (I/f) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
* or hydrolysis under alkaline condition, obtain formula (I/g) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5Be as defined above,
This formula (compound of I/g):
◆ according to the amidation condition of routine with formula (VII) compound treatment:
R
8-NH
2 (Ⅶ)
R wherein
8As the formula I definition,
Obtain formula (I/h) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
8Be as defined above,
At R
8Represent under the particular case of hydrogen atom, according to the normal condition in the organic synthesis, with this formula (I/h) the primary amide functional group of compound is converted into nitrile functionality, obtain formula (I/i) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5Be as defined above,
◆ perhaps according to the normal condition in the organic synthesis, by comprising the reaction sequence of reduction rear oxidation earlier, with this formula (I/g) carboxylic acid functional of compound is converted into aldehyde, obtain formula (I/j) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5Be as defined above,
With this formula (I/j) compound places under the effect of formula (VIII) compound:
R
7-M-X (Ⅷ)
R wherein
7As formula I definition, M represents atoms metal, for example alkali metal atom or magnesium atom, and X represents leavings group, halogen atom for example,
Obtain formula (IX) compound as intermediate:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
With this formula (IX) compound with oxygenant oxidation commonly used in the organic synthesis, obtain formula (I/k) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
◆ perhaps at triethylamine and formula R as defined above
7Under the existence of-OH (VI) compound, handle with hexichol phosphoryl azide thing, obtain formula (I/l) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
At R
7Represent under the particular case of benzyl, in the presence of palladium-carbon, make this formula (I/l) compound carries out hydrogenolysis, obtain formula (I/m) compound, i.e. the formula I compound specific examples:
According to ordinary method, with formula (I/m) primary amine functional group of compound is converted into secondary amine or tertiary amine functional group, obtain formula (I/n) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5, R
8And R
9As the formula I definition,
Self-evident is in this case, R
8And R
9Different times table hydrogen atom,
(I/a) is to (I/n) constitutes the integral body of The compounds of this invention for compound, if necessary, these compounds carry out purifying according to the purifying process of routine, if necessary, can be separated into different isomer according to the separating technology of routine, and randomly be converted into additive salt with pharmaceutically acceptable acid or alkali.
Formula II, (III), (V), (VI), (VII) and (VIII) compound are commercial available compounds, or the compound that obtains according to the currently known methods of organic synthesis.
The invention still further relates to pharmaceutical composition, comprise at least a formula I compound, it optically active isomer or with pharmaceutically acceptable acid or the formed additive salt of alkali as activeconstituents, independent or pharmaceutically acceptable, inert, nontoxic vehicle or carrier in conjunction with one or more.
In according to pharmaceutical composition of the present invention, can mention especially be suitable for oral, parenteral (intravenously, intramuscular or subcutaneous), through skin or transdermal, intranasal, rectum, through tongue, through those of eye or respiratory administration, especially tablet or drageeing, Sublingual tablet, cachet, capsule, lozenge, suppository, creme, ointment, skin gel, injectable or drinkable preparation, aerosol, eye drops or nasal drop etc.
The compounds of this invention has intensive serotonergic 5HT
2B/ 5HT
2CActivity, particularly 5-HT
2C(in conjunction with evidence, The compounds of this invention is especially to K that this receptor had for antagonistic activity
iBe 10
-7To 10
-9NM).Therefore the pharmaceutical composition that contains at least a formula I compound can be used for depression, psychosis, schizophrenia, phobia, anxiety, panic attack, somnopathy, appetite disorder, impulsion and aggressiveness illness, sexual dysfunction and migrainous treatment.
Useful dosage is different because of patient age and body weight, route of administration, disease character and seriousness and any other treatment of being accepted, and its scope is 0.1mg to 500mg every day, in single or divided doses.
The following example is set forth and is limited the present invention absolutely not.
Raw materials used and/or reagent is known product or according to the product of known operation preparation.
The structure of compound described in embodiment and the synthesis step be according to routine spectrophotometry (infrared, NMR, mass spectrum ...) measure.
Embodiment 1: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Steps A: 1-({ [2-(5-chloro-1H-indol-3-yl) ethyl] amino } carbonyl) cyclobutane carboxylate
With 23.1g hydrochloric acid 5-chlorine tryptamines, 17.3g cyclobutane dicarboxylic acid mono ethyl ester, 36ml diisopropylethylamine and 33.7g O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-Tetrafluoroboric acid urea at ambient temperature, in the 200ml methylene dichloride, stirred 20 hours.Wash with water, through dried over sodium sulfate, leach organic phase by diatomite, reduction vaporization can separate obtaining expecting product then.
Step B: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
With the product that obtains in the 32g steps A at 400ml toluene and 35ml POCl
3Solution in reflux.After 3 hours, the reaction mixture concentrating under reduced pressure is dissolved in 300ml ethanol with resistates, slowly adds the 5g sodium borohydride.After 30 minutes, add 300ml water, ethanol is removed in distillation.The resistates dichloromethane extraction, drying, reduction vaporization is converted into hydrochloride with gained oily resistates then in ethanol solution of hydrogen chloride.Filtration is also dry in a vacuum, separates obtaining expecting product.
Fusing point:
Elemental microanalysis:
C H N Cl % calculated value 58.54 6.00 7.59 19.20 % measured values 58.33 5.97 7.61 19.60
Embodiment 2: and hydrochloric acid (R, S)-1-(6-bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses hydrochloric acid 5-bromine tryptamines as reactant in steps A with embodiment 1.
Fusing point:
Elemental microanalysis:
C H N % calculated value 52.25 5.36 6.77 % measured values 52.14 5.41 6.61
Embodiment 3:(+)-1-(6-bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate and hydrochloride thereof
Embodiment 2 products are carried out chirality phase chromatogram (Chiralcel AD) separate, mobile phase is made up of 1000/1 ethanol/diethylamine mixture.
The compound that wash-out comes out contains and surpasses 98% enantiomer, and the effect by ether solution of hydrogen chloride is converted into hydrochloride then.
Fusing point: 226-227 ℃ [α]
D 21 ℃=+23.26 °
Embodiment 4:(-)-1-(6-bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate and hydrochloride thereof
Separate other products obtain in the chromatographic separation process that in embodiment 3, is carried out and be equivalent to expect and contain product and surpass 956 enantiomer, be converted into its hydrochloride then.
Fusing point: 226-227 ℃ [α]
D 21 ℃=-23.18 °
Embodiment 5: hydrochloric acid 1-(6-methyl-2,3,4,9-tetrahydrochysene-1H β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses the hydrochloric acid 5-methyltryptamine as reactant in steps A with embodiment 1.
Fusing point: 235-237 ℃
Elemental microanalysis:
C H N Cl % calculated value 65.41 7.22 8.03 10.16 % measured values 65.27 7.29 7.88 10.46
Embodiment 6: hydrochloric acid 1-(6,7-two chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation is used hydrochloric acid 5 with embodiment 1 in steps A, 6-dichloro tryptamines is as reactant.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl % calculated value 53.55 5.24 6.94 26.34 % measured values 53.88 4.99 6.83 26.10
Embodiment 7: hydrochloric acid 1-(6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses hydrochloric acid 5-methoxytryptamine as reactant in steps A with embodiment 1.
Fusing point: 190-192 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.55 6.91 7.68 9.72 % measured values 62.07 7.10 7.47 9.82
Embodiment 8: hydrochloric acid 1-(2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses tryptamine hydrochloride as reactant in steps A with embodiment 1.
Fusing point: 204-206 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.57 6.92 8.37 10.59 % measured values 64.60 6.98 8.25 10.66
Embodiment 9: hydrochloric acid 1-(6,7-dimethoxy-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation is used hydrochloric acid 5 with embodiment 1 in steps A, the 6-dimethoxytryptamine is as reactant.
Fusing point: 169-170 ℃
Elemental microanalysis:
C H N Cl % calculated value 60.83 6.89 7.09 8.98 % measured values 60.22 7.00 7.05 8.66
Embodiment 10: hydrochloric acid 1-(6,7-two bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation is used hydrochloric acid 5 with embodiment 1 in steps A, 6-dibromo tryptamines is as reactant.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl Br % calculated value 43.89 4.30 5.69 7.20 32.44 % measured values 44.00 4.31 5.67 7.29 32.00
Embodiment 11: hydrochloric acid 1-(6-phenyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
With the compound, 1g phenyl-boron dihydroxide, 1.7g cesium fluoride, 3.2g cesium bromide and 0.7g (triphenyl phosphine) palladium (0) that obtain among the 2g embodiment 2 reflux 20 hours in the 200ml glycol dimethyl ether, purifying (methylene chloride: 97/3), obtain expecting compound after being converted into salt with ether solution of hydrogen chloride on silica gel then.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl % calculated value 69.31 6.67 6.74 8.53 % measured values 68.70 6.45 6.65 8.27
Embodiment 12: hydrochloric acid 1-(7-trifluoromethyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses 6-trifluoromethyl tryptamines as reactant in steps A with embodiment 1.
Fusing point: 241 ℃
Elemental microanalysis:
C H N Cl % calculated value 56.65 5.50 6.95 8.80 % measured values 56.68 5.29 6.82 9.10
Embodiment 13: hydrochloric acid 1-(the 6-tertiary butyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses hydrochloric acid 5-tertiary butyl tryptamines as reactant in steps A with embodiment 1.
Fusing point: lyophilized products
Elemental microanalysis:
C H N Cl % calculated value 64.68 8.12 6.86 8.68 % measured values 64.20 8.16 7.07 8.90
Embodiment 14: hydrochloric acid 1-(7-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses hydrochloric acid 6-methyltryptamine as reactant in steps A with embodiment 1.
Fusing point: 236 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.49 7.60 7.92 10.02 % measured values 64.05 7.86 7.73 10.20
Embodiment 15:1-(6-hydroxyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Under-30 ℃ of inert atmospheres, add the dichloromethane solution of 12ml 1M boron tribromide in the 50ml dichloromethane solution of the compound that in 2g embodiment 7, obtains.After reacting two hours at ambient temperature, reaction mixture 1ml saturated ammonium chloride solution hydrolysis.Leach the gained precipitation, wash with water, dry then, can separate obtaining expecting product.
Fusing point: 215-216 ℃
Elemental microanalysis:
C H N % calculated value 68.77 7.05 8.91 % measured values 67.56 6.88 8.77
Embodiment 16: hydrochloric acid 1-(7-chloro-6-fluoro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses 5-fluoro-6-chlorine tryptamines as reactant in steps A with embodiment 1.
Fusing point: 251-252 ℃
Elemental microanalysis:
C H N Cl % calculated value 58.54 6.00 7 .59 19.20 % measured values 58.33 5.97 7.61 19.60
Embodiment 17: hydrochloric acid 1-(6-fluoro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses 5-fluorine tryptamines as reactant in steps A with embodiment 1.
Fusing point: 212-213 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.27 6.28 7.94 10.05 % measured values 61.25 6.28 7.91 10.38
Embodiment 18: hydrochloric acid 1-(5,6-two chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation is used hydrochloric acid 4 with embodiment 1 in steps A, 5-dichloro tryptamines is as reactant.
Fusing point: 242-243 ℃
Elemental microanalysis:
C H N Cl % calculated value 53.58 5.33 6.87 26.07 % measured values 53.49 5.41 6.72 26.59
Embodiment 19: hydrochloric acid 1-(5,6-two bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation is used hydrochloric acid 4 with embodiment 1 in steps A, 5-dibromo tryptamines is as reactant.
Fusing point: 183-184 ℃
Elemental microanalysis:
C H N Cl Br % calculated value 43.89 4.30 5.69 7.20 32.44 % measured values 44.20 4.40 5.69 7.30 32.00
Embodiment 20: hydrochloric acid 1-(6-chloro-9-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses hydrochloric acid 5-chloro-1-methyltryptamine as reactant in steps A with embodiment 1.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl % calculated value 59.54 6.31 7.31 18.50 % measured values 59.80 6.39 7.09 18.38
Embodiment 21: hydrochloric acid 1-(6-chloro-9-ethyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses hydrochloric acid 5-chloro-1-etryptamine as reactant in steps A with embodiment 1.
Fusing point: 231-232 ℃
Elemental microanalysis:
C H N Cl % calculated value 60.46 6.60 7.05 17.84 % measured values 60.48 6.73 7.02 18.11
Embodiment 22: hydrochloric acid 1-(6-methoxyl group-9-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses hydrochloric acid 5-methoxyl group-1-methyltryptamine as reactant in steps A with embodiment 1.
Fusing point:＞250 ℃
Elemental microanalysis:
C H N Cl % calculated value 63.40 7.18 7.39 9.36 % measured values 62.96 7.62 7.17 9.06
Embodiment 23: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid ring pentyl ester
In the presence of the 1ml titanium tetraisopropylate, with 4.0g embodiment 1 compound reflux in the 80ml cyclopentanol.React after 24 hours, the reaction mixture dilute with water filters then.Use dichloromethane extraction, drying, reduction vaporization makes resistates crystallization from ethanol-diethyl ether-hydrogen chloride mixture then, can separate obtaining expecting product.
Fusing point: 208-209 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.62 6.40 6.84 17.32 % measured values 61.42 6.50 6.65 17.17
Embodiment 24: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid isopropyl ester
Operation uses Virahol to replace cyclopentanol as reagent with embodiment 23.
Fusing point: 244-245 ℃
Elemental microanalysis:
C H N Cl % calculated value 59.54 6.31 7.31 18.50 % measured values 59.57 6.29 7.19 18.72
Embodiment 25: hydrochloric acid 1-(6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid benzyl ester
Operation uses embodiment 7 products as reactant with embodiment 23, uses phenylcarbinol as reagent.
Fusing point: 228-230 ℃
Elemental microanalysis:
C H N Cl % calculated value 67.52 6.37 6.56 8.30 % measured values 67.96 6.49 6.64 8.77
Embodiment 26: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid methyl esters
Operation uses methyl alcohol as reagent with embodiment 23.
Fusing point: 232-233 ℃
Elemental microanalysis:
C H N Cl % calculated value 57.07 5.71 7.83 19.82 % measured values 56.99 5.54 7.50 20.27
Embodiment 27: hydrochloric acid 1-(6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid methyl esters
Operation is with embodiment 23, from embodiment 7 compounds and embodiment 26 reagent.
Fusing point: 208-209 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.62 6.61 7.98 10.11 % measured values 61.56 6.61 7.88 10.23
Embodiment 28: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) hexahydrobenzoic acid ethyl ester
Operation uses the cyclohexane dicarboxylic acid mono ethyl ester as reagent with embodiment 1.
Fusing point: 245-246 ℃
Elemental microanalysis:
C H N Cl % calculated value 60.46 6.60 7.05 17.84 % measured values 60.30 6.52 7.01 18.24
Embodiment 29: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid ethyl ester
Operation uses the pentamethylene mono methyl dicarboxylate as reagent with embodiment 1.
Fusing point: 231-232 ℃
Elemental microanalysis:
C H N Cl % calculated value 59.54 6.31 7.31 18.50 % measured values 59.63 6.32 7.08 18.63
Embodiment 30: hydrochloric acid 1-(6-chloro-9-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid ethyl ester
Operation uses embodiment 29 agents useful for same as reagent in steps A with embodiment 20.
Fusing point: 113-115 ℃
Elemental microanalysis:
C H N Cl % calculated value 66.56 6.98 7.76 9.82 % measured values 66.23 7.16 7.49 10.28
Embodiment 31: hydrochloric acid 1-(6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid ethyl ester
Operation uses embodiment 29 agents useful for same as reagent in steps A with embodiment 7.
Fusing point: 175-176 ℃
Elemental microanalysis:
C H N Cl % calculated value 63.02 7.21 7.34 9.30 % measured values 62.72 7.43 7.17 9.14
Embodiment 32:1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
The suspension of 1g embodiment 1 compound in 15ml water, 30ml alcohol and 5ml 1M sodium hydroxide solution heated 10 hours down at 50 ℃.Reaction mixture cools off then, adds 5ml 1M HCl.The gained precipitation leaches with suction filtration, washes with water, and is dry in a vacuum then, can separate obtaining expecting product.
Fusing point:＞275 ℃
Elemental microanalysis:
C H N Cl % calculated value 63.05 5.62 9.19 11.63 % measured values 62.22 5.67 9.20 11.75
Embodiment 33:1-(6-chloro-9-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses the compound that obtains among the embodiment 20 as reactant with embodiment 32.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.05 6.01 8.79 11.12 % measured values 64.08 5.95 8.67 11.35
Embodiment 34:1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid
Operation uses the compound that obtains among the embodiment 29 as reactant with embodiment 32.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.05 6.01 8.79 11.12 % measured values 64.45 6.13 8.66 11.50
Embodiment 35:1-(2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses the compound that obtains among the embodiment 8 as reactant with embodiment 32.
Fusing point: 280-281 ℃
Elemental microanalysis:
C H N % calculated value 71.09 6.71 10.36 % measured values 71.11 6.88 10.22
Embodiment 36:1-(6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses the compound that obtains among the embodiment 7 as reactant with embodiment 32.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N % calculated value 67.98 6.71 9.33 % measured values 67.96 7.03 8.96
Embodiment 37:1-(6-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 5 compounds as reactant with embodiment 32.
Fusing point:＞250 ℃
Elemental microanalysis:
C H N % calculated value 71.37 7.11 9.79 % measured values 70.98 7.15 9.58
Embodiment 38:1-(7-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 14 compounds as reactant with embodiment 32.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N % calculated value 69.58 6.98 9.54 % measured values 70.10 7.10 9.54
Embodiment 39:1-(the 6-tertiary butyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 13 compounds as reactant with embodiment 32.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N % calculated value 70.13 8.27 8.18 % measured values 70.67 7.98 8.29
Embodiment 40:1-(7-trifluoromethyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 12 compounds as reactant with embodiment 32.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N % calculated value 57.33 5.36 7.87 % measured values 58.28 5.56 7.86
Embodiment 41: hydrochloric acid 1-(6-chloro-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
In the 25ml ethanolic soln of 1g embodiment 1 compound, add 0.3ml methyl-iodide and 0.8gNaHCO
3After reacting 24 hours at ambient temperature, the reaction mixture concentrating under reduced pressure is in the mixture of then that resistates is water-soluble and methylene dichloride.Extraction, drying is filtered, then with the organic phase concentrating under reduced pressure.Crystallization from hydrogenchloride ethanol and diethyl ether solution can access the expection product.
Fusing point: 170-171 ℃
Elemental microanalysis:
C H N Cl % calculated value 59.54 6.31 7.31 18.50 % measured values 59.28 6.24 7.12 18.42
Embodiment 42: hydrochloric acid 1-(6-chloro-2,9-dimethyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 20 compounds as reactant with embodiment 41.
Fusing point: 238-240 ℃
Elemental microanalysis:
C H N Cl % calculated value 60.46 6.60 7.05 17.84 % measured values 60.49 6.57 6.90 18.25
Embodiment 43:1-(6-chloro-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid ethyl ester
Operation uses embodiment 29 compounds as reactant with embodiment 41.
Fusing point: 145-146 ℃
Elemental microanalysis:
C H N Cl % calculated value 59.54 6.31 7.31 18.50 % measured values 59.28 6.24 7.12 18.42
Embodiment 44:1-(6-chloro-2,9-dimethyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid ethyl ester
Operation uses embodiment 30 compounds as reactant with embodiment 41.
Fusing point: 109 ℃
Elemental microanalysis:
C H N Cl % calculated value 67.28 7.26 7.47 9.46 % measured values 67.26 7.46 7.56 10.19
Embodiment 45: hydrochloric acid 1-(6-chloro-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) hexahydrobenzoic acid ethyl ester
Operation uses embodiment 28 compounds as reactant with embodiment 41.
Fusing point: 178-185 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.31 6.86 6.81 17.24 % measured values 61.36 6.77 6.71 16.89
Embodiment 46:1-(2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 8 compounds as reactant with embodiment 41.
Fusing point: 142-144 ℃
Elemental microanalysis:
C H N % calculated value 73.05 7.74 8.97 % measured values 72.66 7.75 8.79
Embodiment 47:1-(6-methoxyl group-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 7 compounds as reactant with embodiment 41.
Fusing point: 124-125 ℃
Elemental microanalysis:
C H N % calculated value 70.15 7.65 8.18 % measured values 70.16 7.64 8.00
Embodiment 48:1-(6-methoxyl group-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid ethyl ester
Operation uses embodiment 31 compounds as reactant with embodiment 41.
Fusing point: 113-114 ℃
Elemental microanalysis:
C H N % calculated value 70.76 7.92 7.86 % measured values 70.21 7.85 7.75
Embodiment 49:1-(2-benzyl-6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses bromotoluene to replace methyl-iodide as reagent with embodiment 41.Fusing point: 155-156 ℃ elemental microanalysis:
C H N Cl % calculated value 70.99 6.43 6.62 8.38 % measured values 70.95 6.51 6.79 9.08
Embodiment 50:1-(6-chloro-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 41 compounds as reactant with embodiment 32.
Fusing point: 174-175 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.05 6.01 8.79 11.12 % measured values 63.97 5.95 8.59 11.45
Embodiment 51:1-(6-chloro-2,9-dimethyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-2-yl) cyclobutane-carboxylic acid
Operation uses embodiment 42 compounds as reactant with embodiment 32.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.96 6.36 8.42 10.65 % measured values 64.40 6.40 8.18 10.91
Embodiment 52:1-(6-chloro-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid
Operation uses embodiment 43 compounds as reactant with embodiment 32.
Fusing point: 171-173 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.96 6.36 8.42 10.65 % measured values 64.59 6.39 8.21 10.77
Embodiment 53:1-(6-chloro-2,9-dimethyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) Cyclopentane carboxylic acid
Operation uses embodiment 44 compounds as reactant with embodiment 32.
Fusing point: 197-198 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.54 6.91 7.68 9.71 % measured values 62.83 7.07 7.64 9.99
Embodiment 54:1-(6-chloro-2-benzyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 49 compounds as reactant with embodiment 32.
Fusing point: 178-180 ℃
Elemental microanalysis:
C H N Cl % calculated value 68.00 6.01 6.89 8.72 % measured values 67.81 6.04 6.91 9.30
Embodiment 55: hydrochloric acid 1-[6-chloro-2-(1H-imidazoles-5-base carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
With 1.84g embodiment 1 compound, 1.8g N-trityl imidazole-4-carboxylic acid, 1.92ml diisopropylethylamine and 1.76g O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-Tetrafluoroboric acid urea stirred 24 hours at ambient temperature.With the dilution of 500ml water, filter, use dichloromethane extraction, then with the organic phase drying, filter, again concentrating under reduced pressure.Resistates crystallization in ethanol-diethyl ether-hydrogen chloride mixture can separate obtaining expecting compound.
Fusing point: 170-171 ℃
Embodiment 56:1-(2-benzoyl-6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses Benzoyl chloride to replace N-trityl imidazole-4-carboxylic acid as reagent with embodiment 55.
Fusing point: 195-196 ℃
Elemental microanalysis:
C H N Cl % calculated value 68.72 5.77 6.41 8.11 % measured values 68.36 5.80 6.26 8.07
Embodiment 57:1-[6-chloro-2-(2-thiophene carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the 2-thiophene chloride as reagent with embodiment 55.
Fusing point: 190-191 ℃
Elemental microanalysis:
C H N Cl S % calculated value 62.36 5.23 6.32 7.24 8.00 % measured values 62.43 5.29 6.30 7.17 7.98
Embodiment 58:1-[6-chloro-2-(3-furoyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the 3-furoyl chloride as reagent with embodiment 55.
Fusing point: 176-177 ℃
Embodiment 59:1-[6-chloro-2-(4-chlorobenzoyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the 4-chloro-benzoyl chloride as reagent with embodiment 55.
Fusing point: 204-205 ℃
Elemental microanalysis:
C H N Cl % calculated value 63.70 5.13 5.94 15.04 % measured values 63.78 5.27 5.95 14.69
Embodiment 60:1-[6-chloro-2-(4-methoxybenzoyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the 4-methoxy benzoyl chloride as reagent with embodiment 55.
Fusing point: 169-170 ℃
Elemental microanalysis:
C H N Cl % calculated value 66.88 5.83 6.00 7.59 % measured values 66.92 5.92 6.02 7.55
Embodiment 61:1-[6-bromo-2-(3-furoyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses embodiment 2 compounds as reactant with embodiment 55, uses the 3-furoyl chloride as reagent.
Fusing point: 178-179 ℃
Elemental microanalysis:
C H N Br % calculated value 58.61 4.92 5.94 16.95 % measured values 58.61 5.11 5.77 16.92
Embodiment 62:1-[6-chloro-2-(2-pyridine carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses 2-Pyridinecarboxylic Acid as reagent with embodiment 55.
Fusing point: 166-167 ℃
Elemental microanalysis:
C H N Cl % calculated value 65.83 5.52 9.60 8.10 % measured values 65.71 5.67 9.58 8.29
Embodiment 63:1-{6-chloro-2-[(4-oxo-4H-pyrans-2-yl) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl } cyclobutane carboxylate
Operation uses 4-oxo-4H-pyrans-3-carboxylic acid as reagent with embodiment 55.
Fusing point: 153-154 ℃
Elemental microanalysis:
C H N Cl % calculated value 63.37 5.10 6.16 7.79 % measured values 63.38 5.17 6.08 7.96
Embodiment 64:1-[6-chloro-2-(3-pyridine carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the 3-pyridine carboxylic acid as reagent with embodiment 55.
Fusing point: 184-185 ℃
Elemental microanalysis:
C H N Cl % calculated value 65.83 5.52 9.60 8.10 % measured values 65.91 5.61 9.53 8.10
Embodiment 65:1-[6-chloro-2-(2-pyrazine carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses 2-pyrazine carboxylic acid as reagent with embodiment 55.
Fusing point: 167-168 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.94 5.28 12.76 8.08 % measured values 63.04 5.40 12.86 8.03
Embodiment 66:1-[6-chloro-2-(2-pyrimidine carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the 2-pyrimidine carboxylic as reagent with embodiment 55.
Fusing point: 158-160 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.94 5.28 12.76 8.08 % measured values 62.04 5.30 12.72 8.11
Embodiment 67:1-[6-chloro-2-(5-isoxazole carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses 5-isoxazole carboxylic acid as reagent with embodiment 55.
Fusing point: 166-167 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.76 5.18 9.82 8.29 % measured values 61.80 5.24 9.74 8.33
Embodiment 68:1-[6-chloro-2-(4-pyridine carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the 4-pyridine carboxylic acid as reagent with embodiment 55.
Fusing point: 205-206 ℃
Elemental microanalysis:
C H N Cl % calculated value 65.83 5.52 9.60 8.10 % measured values 65.85 5.52 9.53 8.07
Embodiment 69:1-[6-bromo-2-(5-isoxazole carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses embodiment 2 compounds as reactant with embodiment 55, uses embodiment 67 reagent as reagent.
Fusing point: 170-171 ℃
Elemental microanalysis:
C H N Br % calculated value 55.94 4.69 8.90 16.92 % measured values 56.02 4.73 8.72 16.67
Embodiment 70:1-[6-chloro-2-(1H-pyrroles-2-base carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses 1H-2-pyrroles's carboxylic acid as reagent with embodiment 55.
Fusing point: 209-210 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.86 5.68 9.87 8.32 % measured values 64.89 5.73 9.76 8.48
Embodiment 71:1-{6-chloro-2-[2-(1H-1,2,3,4-tetrazolium-1-yl) acetyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl } cyclobutane carboxylate
Operation uses 2-(1H-1,2,3,4-tetrazolium-1-yl) acetate as reagent with embodiment 55.
Fusing point: 123-124 ℃
Elemental microanalysis:
C H N Cl % calculated value 56.95 5.23 18.97 8.00 % measured values 57.22 5.36 17.86 7.26
Embodiment 72:1-{6-chloro-2-[(1-methyl isophthalic acid H-imidazol-4 yl) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl } cyclobutane carboxylate
Operation uses 1-methyl isophthalic acid H-imidazoles-4-carboxylic acid as reagent with embodiment 55.
Fusing point: 180-181 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.65 5.71 12.71 8.04 % measured values 63.02 5.67 12.61 8.02
Embodiment 73:(1R)-and 1-[6-chloro-2-(1H-imidazoles-5-base carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Embodiment 55 compounds are upward used ethanol elution at chiral column (CHIRALPAK AD), can separate obtaining expecting product, contain and surpass 98% enantiomer.
Fusing point: 140-142 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.90 5.43 13.12 8.30 % measured values 61.71 5.52 12.82 9.02
Embodiment 74:(1S)-and 1-[6-chloro-2-(1H-imidazoles-5-base carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Second kind of compound that wash-out comes out in the chromatographic separation process that is carried out in embodiment 73 is equivalent to expect product, contains to surpass 98% enantiomer.
Fusing point: 140-142 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.90 5.43 13.12 8.30 % measured values 61.43 5.58 12.79 8.35
Embodiment 75:1-{6-chloro-2-[(1-methyl isophthalic acid H-imidazoles-5-yl) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl } cyclobutane carboxylate
Operation uses 1-methyl isophthalic acid H-imidazole-5-carboxylic acid as reagent with embodiment 55.
Fusing point: 203-204 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.65 5.71 12.71 8.04 % measured values 62.71 5.74 12.73 8.19
Embodiment 76:1-{6-chloro-2-[(5-methyl isophthalic acid H-imidazol-4 yl) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl } cyclobutane carboxylate
Operation uses 5-methyl isophthalic acid H-imidazoles-4-carboxylic acid as reagent with embodiment 55.
Fusing point: 161-162 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.65 5.71 12.71 8.04 % measured values 63.18 6.21 11.93 7.52
Embodiment 77:1-{6-chloro-2-[(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl } cyclobutane carboxylate
Operation is used the 4-methyl isophthalic acid with embodiment 55, and 2,3-thiadiazoles-5-carboxylic acid is as reagent.
Fusing point: 162-163 ℃
Elemental microanalysis:
C H N Cl S % calculated value 57.57 5.05 12.21 7.72 6.99 % measured values 57.49 5.05 12.05 8.04 6.93
Embodiment 78:1-[6-chloro-2-(1,2,3-thiadiazoles-4-base carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses 1,2 with embodiment 55, and 3-thiadiazoles-4-carboxylic acid is as reagent.
Fusing point: 224-225 ℃
Elemental microanalysis:
C H N Cl S % calculated value 56.69 4.76 12.59 7.97 7.21 % measured values 56.90 4.96 12.28 8.00 7.13
Embodiment 79:1-(2-acetyl-6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses Acetyl Chloride 98Min. as reagent with embodiment 55.
Fusing point: 218-219 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.08 6.18 7.47 9.46 % measured values 64.06 6.30 7.34 9.45
Embodiment 80:1-(2-acetyl-6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 7 compounds as reactant with embodiment 55, uses embodiment 79 agents useful for same as reagent.
Fusing point: 180-182 ℃
Elemental microanalysis:
C H N % calculated value 68.09 7.07 7.56 % measured values 68.18 7.28 7.56
Embodiment 81:1-[6-methoxyl group-2-(2-furoyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses embodiment 7 compounds as reactant with embodiment 55, uses 2 furoyl chloride as reagent.
Fusing point: 149-150 ℃
Elemental microanalysis:
C H N % calculated value 68.23 6.20 6.63 % measured values 68.21 6.35 6.66
Embodiment 82:1-[6-chloro-2-(2-furoyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses 2 furoyl chloride as reagent with embodiment 55.
Fusing point: 195-196 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.71 5.43 6.56 8.30 % measured values 64.61 5.55 6.54 8.29
Embodiment 83:1-(2-acetyl-6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 32 compounds as reactant with embodiment 55, uses Acetyl Chloride 98Min. as reagent.
Fusing point:＞250 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.34 5.52 8.08 10.22 % measured values 62.12 5.69 8.01 10.25
Embodiment 84:1-(2-acetyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 35 compounds as reactant with embodiment 55, uses Acetyl Chloride 98Min. as reagent.
Fusing point: 244-246 ℃
Elemental microanalysis:
C H N % calculated value 69.21 6.45 8.97 % measured values 69.03 6.70 8.69
Embodiment 85: hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene methane amide
Under 0 ℃, in the solution of 1g embodiment 1 compound in 20ml diox, 20ml water and 10ml 1M sodium hydroxide solution, add the 0.8g carbonic acid tert-butyl ester (tert-butylpyrocarbonate).React after 4 hours, the reaction mixture dilute with water is with 5% citric acid solution acidifying.Use ethyl acetate extraction, the organic phase drying, concentrating under reduced pressure, gained resistates are then with 50ml hydrogen furans and the dilution of 0.5ml N-methylmorpholine.After mixture is cooled to-10 ℃, add the 0.3ml Vinyl chloroformate, add 0.2ml 28% solution of ammonium hydroxide then.React after 12 hours, distillation removes and desolvates.Then with resistates water-soluble/dichloromethane mixture in.Decant, drying, concentrating under reduced pressure, resistates are used hydrogenchloride ethanol and diethyl ether solution solution-treated then, can obtain required product with hydrochloride form.
Fusing point: 229-230 ℃
Elemental microanalysis:
C H N Cl % calculated value 56.48 5.63 12.35 20.84 % measured values 56.30 5.65 12.07 20.81
Embodiment 86:1-[1-(aminocarboxyl) cyclobutyl]-6-chloro-1,3,4,9-tetrahydrochysene-2H-β-Ka Lin-2-carboxylic acid tert-butyl ester
This product is the common property thing that obtains during embodiment 85 compounds synthesize.
Fusing point: 229-230 ℃
Elemental microanalysis:
C H N Cl % calculated value 62.45 6.49 10.40 8.78 % measured values 62.53 6.53 10.12 8.80
Embodiment 87:1-[1-(aminocarboxyl) cyclobutyl]-6-chloro-1,3,4,9-tetrahydrochysene-2H-β-Ka Lin-2-carboxylic acid, ethyl ester
Under-10 ℃, in the solution of 1g embodiment 32 compounds in 50ml tetrahydrofuran (THF) and 0.5ml N-methylmorpholine, add the 0.3ml Vinyl chloroformate, add 0.2ml 28% solution of ammonium hydroxide then.React after 12 hours, distillation removes and desolvates; Then with resistates water-soluble/dichloromethane mixture.By decant, drying and concentrating under reduced pressure, separate obtaining expecting product.
Fusing point: 200-201 ℃
Elemental microanalysis:
C H N Cl % calculated value 60.72 5.90 11.18 9.43 % measured values 60.49 6.00 10.82 9.29
Embodiment 88:1-(6-chloro-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene methane amide
Operation uses embodiment 33 compounds as reactant with embodiment 87.
Fusing point: 129-130 ℃
Elemental microanalysis:
C H N Cl % calculated value 64.25 6.34 13.22 11.16 % measured values 64.03 6.43 12.47 11.09
Embodiment 89: hydrochloric acid 1-(6-chloro-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclohexane carboxamide
Operation uses embodiment 45 compounds as reactant with embodiment 87.
Fusing point: 175-176 ℃
Embodiment 90:1-(2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene methane amide
Operation uses embodiment 46 compounds as reactant and use amino-formaldehyde (aminocarbaldehyde) with embodiment 87.
Fusing point: 145-146
Embodiment 91:1-(2-formyl-6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene methane amide
In the presence of sodium methylate, in dimethyl formamide, carry out the reaction between embodiment 1 compound and the amino-formaldehyde, can access required product.
Fusing point:＞260 ℃
Elemental microanalysis:
C H N Cl % calculated value 61.54 5.47 12.66 10.68 % measured values 61.36 5.61 12.26 10.75
92: two hydrochloric acid 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl)-N-[2-(dimethylamino) ethyls of embodiment] the tetramethylene methane amide
Operation uses 2-(N, N-dimethylamino) ethamine to replace ammonium hydroxide as reagent with embodiment 85.
Fusing point: 229-231 ℃
Elemental microanalysis:
C H N Cl % calculated value 53.64 6.53 12.51 23.75 % measured values 53.13 6.39 12.31 24.35
Embodiment 93:6-chloro-1-[1-({ [2-(dimethylamino) ethyl] amino } carbonyl) cyclobutyl]-1,3,4,9-tetrahydrochysene-2H-β-Ka Lin-2-carboxylic acid tert-butyl ester
This product is the common property thing during embodiment 92 compounds synthesize.
Fusing point: 84-85 ℃
Elemental microanalysis:
C H N Cl % calculated value 63.21 7.43 11.79 7.46 % measured values 62.72 7.18 11.63 7.52
Embodiment 94:1-[2-(tertbutyloxycarbonyl)-6-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane-carboxylic acid
Add the 5.52g two carbonic acid tert-butyl esters in the solution of the compound that in 6.5g embodiment 37, obtains in 50mml diox and 25ml 1M sodium hydroxide solution.After reacting 20 hours at ambient temperature, add 50ml ethyl acetate and 100ml water, reaction mixture is acidified to pH 2.3 with KHS04 solution then.Leach the precipitation that is generated, wash with water, drying can separate obtaining expecting product.
Fusing point: 217-218 ℃
Elemental microanalysis:
C H N % calculated value 68.73 7.34 7.29 % measured values 68.42 7.28 7.18
Embodiment 95:N-[2-(dimethylamino) ethyl]-1-(6-methoxyl group-2-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene methane amide
At a large amount of excessive N, under the existence of N-(dimethylamino) ethamine, heat treated embodiment 47 compounds obtain this product.
Fusing point: 187-188 ℃
Elemental microanalysis:
C H N % calculated value 68.72 8.39 14.57 % measured values 68.48 8.31 14.52
Embodiment 96:1-{6-chloro-2-[(3-pyridine amino) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl } cyclobutane carboxylate
Under inert atmosphere, with the 60ml toluene solution reflux of 0.9g 3-pyridine carbonyl trinitride 1 hour 30 minutes.After mixture returns to envrionment temperature, add the compound diluted with the 60ml methylene dichloride, obtain among the 1.65g embodiment 1.Reaction mixture stirred 20 hours at ambient temperature, leached the precipitation that is generated then, washing, and subsequent drying can separate obtaining expecting product.
Fusing point: 126-128 ℃
Embodiment 97:1-(1-([(benzyloxy) carbonyl] amino } cyclobutyl)-the 6-methyl isophthalic acid, 3,4,9-tetrahydrochysene-2H-β-Ka Lin carboxylic acid tert-butyl ester
With the vlil of compound in 3.3ml hexichol phosphoryl azide thing, 2.1ml triethylamine and 5.2ml phenylcarbinol that obtains among the 2.8g embodiment 94.Handle the back and separate (methylene chloride), can separate obtaining expecting product in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel.
Fusing point: 219-220 ℃
Elemental microanalysis:
C H N % calculated value 71.14 7.20 8.58 % measured values 70.38 7.17 8.16
Embodiment 98: hydrochloric acid 1-(6-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) encircles butylamine
Steps A 1:1-(6-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutyl carboxylamine phenylester
The compound that obtains among the 0.9g embodiment 97 is dissolved in the 50ml ethyl acetate, to wherein feeding gaseous hydrogen chloride.React after one hour, leach the precipitation that is generated, with the diethyl ether washing, drying can separate obtaining expecting product.
Fusing point: 244-245 ℃
Step B1: hydrochloric acid 1-(6-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) encircles butylamine
In the presence of 10% palladium-carbon, the effect by hydrogen in 50ml ethanol is carried out hydrogenation to the compound that obtains in the 0.5g steps A 1.Filter, the crystallization from diethyl ether then of concentrating under reduced pressure, resistates can separate obtaining expecting product.
Fusing point: 180 ℃
Embodiment 99: hydrochloric acid 1-(the 6-tertiary butyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) encircles butylamine
Operation with embodiment 94, embodiment 97, be embodiment 98 steps A 1 and B1 then, use embodiment 39 compounds as reactant.
Fusing point: 245 ℃
Elemental microanalysis:
C H N Cl % calculated value 66.35 8.45 12.58 10.62 % measured values 66.80 8.37 11.96 9.91
Embodiment 100:1-(6-chloro-4,9-dihydro-3H-β-Ka Lin-1-yl) cyclobutane carboxylate
Obtain this product according to embodiment 1 described scheme, but sodium borohydride of no use carries out the reductive final step.
Fusing point: 141-142 ℃
Elemental microanalysis:
C H N Cl % calculated value 65.35 5.79 8.47 10.72 % measured values 65.37 5.76 8.44 10.94
Embodiment 101:1-(6-bromo-4,9-dihydro-3H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 2 used reactants as reactant with embodiment 100.
Fusing point: 132-133 ℃
Elemental microanalysis:
C H N Br % calculated value 57.61 5.10 7.46 21.29 % measured values 57.64 5.22 7.45 21.05
Embodiment 102:1-(4,9-dihydro-3H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 8 used reactants as reactant with embodiment 100.
Fusing point: 121-122 ℃
Elemental microanalysis:
C H N % calculated value 72.95 6.80 9.45 % measured values 72.88 6.93 9.48
Embodiment 103:1-(6-methyl-4,9-dihydro-3H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 5 used reactants as reactant with embodiment 100.
Fusing point: 101-103 ℃
Elemental microanalysis:
C H N % calculated value 73.52 7.14 9.03 % measured values 73.56 7.23 8.93
Embodiment 104:1-(6-methoxyl group-4,9-dihydro-3H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 7 used reactants as reactant with embodiment 100.
Fusing point: 229-230 ℃
Elemental microanalysis:
C H N % calculated value 69.92 6.79 8.58 % measured values 69.51 6.63 8.33
Embodiment 105:1-(6-chloro-9-ethyl-4,9-dihydro-3H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 21 used reactants as reactant with embodiment 100.
Fusing point: 115-116 ℃
Elemental microanalysis:
C H N Cl % calculated value 66.94 6.46 7.81 9.88 % measured values 67.82 6.62 7.85 9.94
Embodiment 106:1-(6-methoxyl group-9H-β-Ka Lin-1-yl) cyclobutane carboxylate refluxes 1.5g embodiment 104 compounds 96 hours in 10ml dimethylbenzene in the presence of 0.25g 10% palladium-carbon.Filter, concentrating under reduced pressure separates (dichloromethane/ethyl acetate: 80/20), can separate obtaining expecting product in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel then.
Fusing point: 128-129 ℃
Elemental microanalysis:
C H N % calculated value 70.35 6.21 8.64 % measured values 70.36 6.22 8.63
Embodiment 107:1-(9H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 102 compounds as reactant with embodiment 106.
Fusing point: 144-145 ℃
Elemental microanalysis:
C H N % calculated value 73.45 6.16 9.52 % measured values 73.51 6.22 9.20
Embodiment 108:1-(6-chloro-9-ethyl-9H-β-Ka Lin-1-yl) cyclobutane carboxylate
Operation uses embodiment 105 compounds as reactant with embodiment 106.
Fusing point: 131-132 ℃
Elemental microanalysis:
C H N Cl % calculated value 67.32 5.93 7.85 9.93 % measured values, 67.19 6.08 7.57 10.12 embodiment 109:1-(9H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid
Operation uses embodiment 107 compounds as reactant with embodiment 32.
Fusing point: 115-116 ℃
Elemental microanalysis:
C H N % calculated value 72.17 5.30 10.52 % measured values 71.58 5.36 10.38
110: two hydrochloric acid 1-(9H-β-Ka Lin-1-yl)-N-[2-(dimethylamino) ethyls of embodiment] the tetramethylene methane amide
At a large amount of excessive N, under the existence of N-(dimethylamino) ethamine, heat treated embodiment 107 compounds obtain this product.
Fusing point: lyophilized products
Embodiment 111:1-(6-methoxyl group-9H-β-Ka Lin-1-yl)-N-[2-(dimethylamino) ethyl] the tetramethylene methane amide
Operation uses embodiment 106 compounds as reactant with embodiment 110.
Fusing point: lyophilized products
Embodiment 112:1-(6-hydroxyl-9H-β-Ka Lin-1-yl)-N-[2-(dimethylamino) ethyl] the tetramethylene methane amide
According to embodiment 15 described condition Processing Example 111 compounds.
Fusing point: 182-183
Embodiment 113: hydrochloric acid 1-[6-(trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Steps A: 2-[4-(triethylsilyl)-3-butynyl]-1H-isoindole-1,3 (2H)-diketone
The 50ml dimethyl formamide solution that in the suspension of 72.3g phthalic imidine acid potassium (potassium phthalimidate) in the 450ml dimethyl formamide, adds 108g (4-triethyl silyl fourth-3-alkynes-1-alcohol) tosylate.At 60 ℃ after following 4 hours, dimethyl formamide is removed in distillation.Resistates is dissolved in 1/1 methylene dichloride/water mixture, extraction, drying is filtered, and concentrating under reduced pressure can access the expection product then.
Step B:2-(2-[2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl] ethyl }-1H-isoindole-1,3 (2H)-diketone
Under inert atmosphere, with the 200ml dimethyl formamide solution of the compound, 0.75g dichloro palladium-diphenyl phosphine-ferrocene, 0.76g lithium chloride and the 3.81g sodium bicarbonate that obtain in 5.16g 2-iodo-4-5-trifluoromethylaniline, the 11.6g steps A 100 ℃ of heating down.After 30 hours, distillation removes and desolvates.With resistates water-soluble/dichloromethane mixture, extraction, drying is filtered, then concentrating under reduced pressure.Separate (methylene dichloride) in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, can separate obtaining expecting product, crystallization in heptane.
Fusing point:＜25 ℃
Step C:2-[2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl] ethamine
With the 150ml ethanolic soln reflux of the compound that obtains among the 6.25g step B and 3.5ml hydrazine one hour, with 20ml 4N HCl dilution, reflux was one hour once more then.After the dilution of 100ml water, remove ethanol in a vacuum.Add sodium hydroxide solution and give resistates, use dichloromethane extraction with alkalescence.Merging and dried organic moiety under reduced pressure concentrate, and can separate obtaining expecting product.
Fusing point: 56 ℃
Step D:2-[5-(trifluoromethyl)-1H-indol-3-yl] ethamine
In the presence of 1g 3 molecular sieves, the compound that obtains among the 3.8g step C was stirred 72 hours in the tetrahydrofuran solution of 200ml tetrahydrofuran (THF) and 10ml 1M tetrabutyl ammonium fluoride at ambient temperature.Leach resin, be evaporated to driedly, then resistates is dissolved in 100ml 1N HCl, use washed with dichloromethane.Give then and contain water with alkalescence, use dichloromethane extraction, the organic phase after the merging is operated with ordinary method.Products therefrom crystallization in ethanol-diethyl ether-hydrogen chloride mixture obtains hydrochloride.
Fusing point:＞250 ℃
Step e: hydrochloric acid 1-[6-(trifluoromethyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate
Operation uses the product that obtains among the step D as reactant with embodiment 1.
Fusing point: 237 ℃
Elemental microanalysis:
C H N Cl % calculated value 56.65 5.50 6.95 8.80 % measured values 56.62 5.60 6.92 8.90
Embodiment 114: hydrochloric acid [1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutyl] methyl alcohol
10g embodiment 1 compound is dissolved in the 400ml tetrahydrofuran (THF), under nitrogen atmosphere, in 30 minutes, adds 2g LiAlH
4Reacted 3 hours, the reaction mixture hydrolysis leaches inorganic salt with suction filtration then, and filtrate is evaporated to dried.Obtain the 7.9g product, in ethanol-diethyl ether-hydrogen chloride mixture, be translated into hydrochloride then, obtain expecting product.
Embodiment 115:1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene formonitrile HCN
Steps A: 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene formaldehyde
Mixture in the 100ml methylene dichloride stirred 1 hour down at 0 ℃ with 2.8g embodiment 2 compounds and 3.6g Dess-Martin reagent.Return to envrionment temperature, evaporation removes and desolvates, and separates (methylene dichloride) in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel then, can separate obtaining expecting product.
Step B:1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl)-N-hydroxyl tetramethylene methane amide
With the solution stirring of compound in 120ml ethanol, 0.54ml triethylamine and 0.27g oxammonium hydrochloride that obtain in the 1.2g steps A 6 hours, concentrating under reduced pressure then.Separate (dichloromethane/ethyl acetate: 98/2), can separate obtaining expecting product in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel.
Step C:1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) tetramethylene formonitrile HCN
At ambient temperature, the compound that obtains among the 0.9g step B was stirred 2 hours in 10ml diox, 0.8ml pyridine and 0.42ml trifluoroacetic acid anhydride solution.After evaporation removes and desolvates, resistates is separated (dichloromethane/ethyl acetate: 96/4), can separate obtaining expecting product, crystallization in heptane in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel.
Fusing point: 218-219 ℃
Elemental microanalysis:
C H N Cl % calculated value 67.25 5.64 14.70 12.41 % measured values 67.01 5.80 14.56 12.50
Embodiment 116: hydrochloric acid 1-[1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutyl]-1-acetone
Steps A: 1-[1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutyl-1-propyl alcohol
In the presence of the tetrahydrofuran solution of 15ml 1M ethylmagnesium bromide, under inert atmosphere, the 150ml tetrahydrofuran solution of the compound that obtains in 2.32g embodiment 115 steps A was stirred 4 hours down at-30 ℃.After returning to envrionment temperature, mixture is handled according to ordinary method, and concentrating under reduced pressure can separate obtaining expecting product then.
Step B:1-[1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutyl]-1-acetone
Scheme according to embodiment 115 steps A is handled the compound that obtains in the 1g steps A, can access the expection product.
Fusing point: 168-170 ℃ (decomposition)
Elemental microanalysis:
C H N Cl % calculated value 61.20 6.28 7.93 20.07 % measured values 61.31 6.44 7.65 20.02
The pharmacological research of The compounds of this invention
Embodiment 117: rat erection test, (1.25mg/kg s.c.) brings out erection with Ro60-0175
(" European pharmacology magazine " 1997,325 9-12) can be estimated the ability that pharmaceutical agent suppresses the erection brought out by Ro 60-0175, and Ro 60-0175 is a kind of selectivity 5-HT in this test
2cAgonist.Therefore restraining effect is about 5-HT
2cThe omen of the antagonistic activity of acceptor.Is that (Iffa-Credo, France) administration individually are placed on the synthetic glass observation box respectively (in 7.5 * 18 * 30cm) to rat then with product or its carrier to the male Wistar at experiment heavy 120-140g on the same day.After 30 minutes, (1.25mg/kg s.c.) to animals administer, adds up the erection number that reaches in afterwards 30 minutes with Ro 60-0175.In this test, the ID that The compounds of this invention embodiment 1,6,7 and 18 compounds are showed
50s(suppress dosage
50, with mg/kg, s.c. represents) and be respectively 0.9,0.9,1.1 and 0.5.Therefore The compounds of this invention shows strong activity in this respect.
Embodiment 118: antagonism 5HT
2BActivity
From expressing human 5HT
2BThe CHO-5-HT of serotonin receptor
2BCell makes film, it is suspended in measures damping fluid (Tris-HCl, 50mM, pH=7.4, CaCl
2, 4mM) in, standby-80 times storages.In in conjunction with experiment, (ultimate density is the former material of 50 μ g/ml) with 50 μ l[with 400 μ l film suspensions
3H]-LSD (ultimate density is 1nM) and 50 μ l competition medicine cultivated 1 hour down at 37 ℃.On the GF/B Unfilters that cultivates with 0.1% polymine in advance, filter.
In this test, The compounds of this invention demonstrates antagonism 5HT
2BActivity, the IC that is showed
50In the nmole level.
Embodiment 119: pharmaceutical composition: tablet
1000 tablet preparation prescriptions, every contains 5mg activeconstituents embodiment 1 compound 5g hydroxypropylcellulose 2g wheat starch 10g lactose 100g Magnesium Stearate 2g talcum 2g
Claims (22)
1, formula I compound:
Wherein:
Represent a singly-bound or two key, randomly can give carry them ring with aromatic character,
R
1The group of representative is selected from:
◆ hydrogen,
◆ straight or branched (C
1-C
6) alkyl,
◆-R
6-aryl ,-R
6-cycloalkyl, R
6-heterocycle, wherein R
6Base is represented straight or branched (C
1-C
6) alkylidene group,
◆-CO
2R
7, R wherein
7Represent straight or branched (C
1-C
6) alkyl, aryl, cycloalkyl, heterocycle ,-R
6-aryl ,-R
6-cycloalkyl or-R
6-heterocycle, wherein R
6Be as defined above,
◆-COR
8, R wherein
8Represent hydrogen atom, straight or branched (C
1-C
6) alkyl, aryl, cycloalkyl, heterocycle ,-R
6-aryl ,-R
6-cycloalkyl or-R
6-heterocycle, wherein R
6Be as defined above,
◆-CONH-R
8, R wherein
8Be as defined above,
Perhaps ought carry R
1Nitrogen-atoms when having carried cyclic olefinic bond, R
1Do not exist,
R
2The group of representative is selected from:
◆ cyano group,
◆-CO
2R
8, R wherein
8Be as defined above,
◆-CONHR
8, R wherein
8Be as defined above,
◆ single (C
1-C
6) alkylamino (C
1-C
6) alkyl amino-carbonyl, two (C
1-C
6) alkylamino (C
1-C
6) alkyl amino-carbonyl, the moieties of each group can be a straight or branched,
◆-NR
8R
9, R wherein
8Be as defined above, R
9Representative is as R
8Defined group,
◆-NH-CO
2R
7, R wherein
7Be as defined above,
◆-COR
8, R wherein
8Be as defined above,
R
3And R
4Form (C together
3-C
10) cycloalkyl,
R
5Represent hydrogen atom, straight or branched (C
1-C
6) alkyl or aryl-(C
1-C
6) alkyl, the latter's moieties can be a straight or branched,
Ra, Rb, Rc and Rd can be identical or different, and the group of representative is selected from hydrogen, halogen, straight or branched (C independently of one another
1-C
6) alkyl, hydroxyl, straight or branched (C
1-C
6) alkoxyl group, straight or branched three halo (C
1-C
6) alkyl, straight or branched three halo (C
1-C
6) alkoxyl group, nitro, cyano group, amino, straight or branched (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino--wherein each moieties can be a straight or branched--, aryl, aryl-(C
1-C
6) alkyl--wherein moieties can be a straight or branched--, carboxyl, straight or branched (C
1-C
6) alkyl-carbonyl oxygen base, straight or branched (C
1-C
6) acyl group, aryloxy and aryl-(C
1-C
6) alkoxyl group--wherein the alkoxyl group part can be a straight or branched--,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali,
Self-evident:
That-" cycloalkyl " is understood that is single-or two-cyclic group, it is saturated (perhaps randomly containing the one or more degrees of unsaturation of ring system with aromatic character of can not giving), contain 3 to 10 carbon atoms, randomly replaced by one or more identical or different groups, substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl and straight or branched (C
1-C
6) alkoxyl group,
-" aryl " is understood that phenyl, naphthyl, tetralyl, dihydro naphthyl, indenyl or 2, and 3-dihydro indenyl is randomly replaced by one or more identical or different groups separately, and substituting group is selected from halogen, hydroxyl, cyano group, nitro, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, amino, straight or branched (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino--wherein each moieties can be a straight or branched--, aryloxy, aryl-(C
1-C
6) alkoxyl group--wherein alkoxyl group part can be straight or branched--, straight or branched three halo (C
1-C
6) alkyl, straight or branched (C
1-C
6) acyl group, straight or branched (C
1-C
6) alkoxy carbonyl, straight or branched (C
1-C
6) alkyl amino-carbonyl and oxo,
That-" heterocycle " is understood that is saturated or undersaturated, single-or two-cyclic group, have aromatics or non-aromatic character, have 5 to 12 annular atomses, contain one, heteroatoms that two or three are identical or different, heteroatoms is selected from oxygen, nitrogen and sulphur, heterocycle is understood that and can be randomly replaced by one or more identical or different groups that substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, nitro, oxo and amino is (optional by one or two straight or branched (C
1-C
6) the alkyl replacement).
2, according to the formula I compound of claim 1, it is characterized in that R
3With R
4Form saturated, monocyclic (C together
3-C
10) cycloalkyl, it is randomly replaced by one or more identical or different groups, and substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl and straight or branched (C
1-C
6) alkoxyl group,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
3, according to the formula I compound of claim 1 or 2, it is characterized in that R
3With R
4Form replacement, saturated, monocyclic (C together
4-C
6) cycloalkyl,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
4, the formula I compound any according to claim 1 to 3 is characterized in that R
3With R
4Form cyclobutyl together,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
5, according to the formula I compound of claim 1, it is characterized in that R
1Represent hydrogen atom or-COR
8Base, wherein R
8As the formula I definition,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
6, according to the formula I compound of claim 1 or 5, it is characterized in that R
1Representative-COR
8aBase, wherein R
8aRepresent aryl or heterocycle,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
7, according to the formula I compound of claim 1, it is characterized in that R
2Represent Shi-CO
2R
8Base, wherein R
8As the formula I definition,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
8, according to the formula I compound of claim 1 or 7, it is characterized in that R
2Represent Shi-CO
2R
8bBase, wherein R
8bRepresent straight or branched (C
1-C
6) alkyl or cycloalkyl,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
9, according to the formula I compound of claim 1 or 8, it is characterized in that R
2Represent Shi-CO
2R
8bBase, wherein R
8bRepresent ethyl or cyclopentyl,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
10, according to the formula I compound of claim 1, it is characterized in that R
5Represent hydrogen atom,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
11,, it is characterized in that they have formula (I ') structure according to the formula I compound of claim 1:
Wherein:
R
1, R
2, R
3, R
4, R
5, Ra, Rb, Rc and Rd such as formula I definition,
Their isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
12, according to the formula I compound of claim 1, it is 1-(6-chloro-2,3,4, a 9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane-carboxylic acid ring pentyl ester,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
13, according to the formula I compound of claim 1, it is 1-(6-bromo-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
14, according to the formula I compound of claim 1, it is 1-[6-chloro-2-(1H-imidazoles-5-base carbonyl)-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl] cyclobutane carboxylate,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
15, according to the formula I compound of claim 1, it is 1-(6-methyl-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
16, according to the formula I compound of claim 1, it is 1-(5,6-two chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
17, according to the formula I compound of claim 1, it is 1-(6-chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
18, according to the formula I compound of claim 1, it is 1-(6,7-two chloro-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
19, according to the formula I compound of claim 1, it is 1-(6-methoxyl group-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-1-yl) cyclobutane carboxylate,
Its isomer, and with pharmaceutically acceptable acid or the formed additive salt of alkali.
20, the preparation method of formula I compound is characterized in that using the formula II compound as raw material:
Wherein Ra, Rb, Rc, Rd and R
5As the formula I definition,
According to the synthesis condition that is applicable to peptide coupling type, make the reaction of this formula II compound and formula III compound:
R wherein
3And R
4As the formula I definition,
Obtain the formula IV compound:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
In the presence of phosphoryl chloride, in a kind of solvent, for example toluene or benzene are handled this formula IV compound, obtain formula (I/a) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
This formula (compound of I/a):
★ is according to the normal condition in organic synthesis reduction, obtain formula (I/b) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
Under alkaline condition, in the presence of formula (V) compound:
R
1-X (Ⅴ)
R wherein
1As the formula I definition, X represents leavings group commonly used in the organic synthesis,
To this formula (I/b) compound is handled, obtain formula (I/c) compound, i.e. the formula I compound specific examples:
★ or be subjected in the organic synthesis effect of oxygenant commonly used, obtain formula (I/d) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
3, R
4And R
5Be as defined above,
All formulas (I/a), (I/b), (I/c) and (the compound constitutional formula of I/d) (I/e) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5As the formula I definition,
This formula (compound of I/e)
* in the presence of Lewis acid and formula VI compound:
R
7-OH (Ⅵ)
R wherein
7As the formula I definition,
Be subjected to transesterification, obtain formula (I/f) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
* or hydrolysis under alkaline condition, obtain formula (I/g) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5Be as defined above,
This formula (compound of I/g):
◆ according to the amidation condition of routine with formula (VII) compound treatment:
R
8-NH
2 (Ⅶ)
R wherein
8As the formula I definition,
Obtain formula (I/h) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
8Be as defined above,
At R
8Represent under the particular case of hydrogen atom, according to the normal condition in the organic synthesis, with this formula (I/h) the primary amide functional group of compound is converted into nitrile functionality, obtain formula (I/i) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5Be as defined above,
◆ perhaps according to the normal condition in the organic synthesis, by comprising the reaction sequence of reduction rear oxidation earlier, with this formula (I/g) carboxylic acid functional of compound is converted into aldehyde, obtain formula (I/j) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4And R
5Be as defined above,
With this formula (I/j) compound places under the effect of formula (VIII) compound:
R
7-M－X (Ⅷ)
R wherein
7As formula I definition, M represents atoms metal, for example alkali metal atom or magnesium atom, and X represents leavings group, halogen atom for example,
Obtain formula (IX) compound as intermediate:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
With this formula (IX) compound with oxygenant oxidation commonly used in the organic synthesis, obtain formula (I/k) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
◆ perhaps at triethylamine and formula R as defined above
7Under the existence of-OH (VI) compound, handle, obtain formula (I/1) compound, i.e. the formula I compound specific examples with hexichol phosphoryl azide thing:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5And R
7Be as defined above,
At R
7Represent under the particular case of benzyl, in the presence of palladium-carbon, make this formula (I/l) compound carries out hydrogenolysis, obtain formula (I/m) compound, i.e. the formula I compound specific examples:
According to ordinary method, with formula (I/m) primary amine functional group of compound is converted into secondary amine or tertiary amine functional group, obtain formula (I/n) compound, i.e. the formula I compound specific examples:
Wherein Ra, Rb, Rc, Rd, R
1, R
3, R
4, R
5, R
8And R
9As the formula I definition,
Self-evident is in this case, R
8And R
9Different times table hydrogen atom,
(I/a) is to (I/n) constitutes the integral body of The compounds of this invention for compound, if necessary, these compounds carry out purifying according to the purifying process of routine, if necessary, can be separated into different isomer according to the separating technology of routine, and randomly be converted into additive salt with pharmaceutically acceptable acid or alkali.
21, pharmaceutical composition, comprise at least a according to any one the formula I compound of claim 1 to 17 as activeconstituents, independent or pharmaceutically acceptable, inert, nontoxic vehicle or carrier in conjunction with one or more.
22, according to the pharmaceutical composition of claim 19, comprise at least a activeconstituents any, be used for depression, psychosis, schizophrenia, phobia, anxiety, panic attack, somnopathy, appetite disorder, impulsion and aggressiveness illness, sexual dysfunction and migrainous treatment according to claim 1 to 17.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9909576 | 1999-07-23 | ||
| FR9909576A FR2796644B1 (en) | 1999-07-23 | 1999-07-23 | NOVEL BETA-CARBOLINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1282743A true CN1282743A (en) | 2001-02-07 |
Family
ID=9548447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00121615A Pending CN1282743A (en) | 1999-07-23 | 2000-07-21 | New beta-carbiline compounds, their preparation method and medicine composition conterning same |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US6350757B1 (en) |
| EP (1) | EP1070716A1 (en) |
| JP (1) | JP2001072679A (en) |
| KR (1) | KR20010049859A (en) |
| CN (1) | CN1282743A (en) |
| AU (1) | AU762958B2 (en) |
| BR (1) | BR0003105A (en) |
| CA (1) | CA2314473A1 (en) |
| EA (1) | EA004140B1 (en) |
| FR (1) | FR2796644B1 (en) |
| HU (1) | HUP0002843A3 (en) |
| MX (1) | MXPA00007058A (en) |
| NO (1) | NO20003764L (en) |
| NZ (1) | NZ505903A (en) |
| PL (1) | PL341549A1 (en) |
| ZA (1) | ZA200003702B (en) |
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| CN102711467A (en) * | 2009-09-23 | 2012-10-03 | 梅迪维新技术公司 | Pyrido(3,4-b)indoles and methods of use |
| CN102724875A (en) * | 2009-09-23 | 2012-10-10 | 梅迪维新技术公司 | Pyrido[3,4-b]indoles and methods of use |
| CN102046175B (en) * | 2008-03-12 | 2015-08-12 | 细胞内治疗公司 | The heterocyclic fused gamma-carbolines solid replaced |
| US9260429B2 (en) | 2008-03-24 | 2016-02-16 | Medivation Technologies, Inc. | Pyrido[3,4-B]indoles and methods of use |
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| UA74826C2 (en) * | 2000-05-17 | 2006-02-15 | Ortho Mcneil Pharm Inc | ?-carboline derivatives as phosphodiesterase inhibitors |
| US20040253891A1 (en) * | 2000-09-12 | 2004-12-16 | Schierenbeck Alan W. | Composite structure for protective garment |
| TWI329111B (en) | 2002-05-24 | 2010-08-21 | X Ceptor Therapeutics Inc | Azepinoindole and pyridoindole derivatives as pharmaceutical agents |
| ATE414082T1 (en) * | 2003-04-29 | 2008-11-15 | Oscient Pharmaceuticals | ANTIBIOTIC TETRAHYDRO-B-CARBOLINE DERIVATIVES |
| ES2427166T3 (en) * | 2003-06-23 | 2013-10-29 | Ono Pharmaceutical Co., Ltd. | Novel tricyclic heterocyclic compound |
| US20050143371A1 (en) * | 2003-07-23 | 2005-06-30 | Pharmacia Corporation | Beta-carboline compounds and analogues thereof as mitogen-activated protein kinase-activated protein kinase-2 inhibitors |
| US7855295B2 (en) | 2004-01-23 | 2010-12-21 | Novartis Vaccines And Diagnostics, Inc. | Tetrahydrocarboline compounds as anticancer agents |
| US7767689B2 (en) * | 2004-03-15 | 2010-08-03 | Ptc Therapeutics, Inc. | Carboline derivatives useful in the treatment of cancer |
| US8076352B2 (en) | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
| US8076353B2 (en) | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Inhibition of VEGF translation |
| UA92317C2 (en) | 2004-03-15 | 2010-10-25 | Пи-Ти-Си ТЕРАПЬЮТИКС, ИНК. | Carboline derivatives useful in the inhibition of angiogenesis |
| AR051780A1 (en) * | 2004-11-29 | 2007-02-07 | Japan Tobacco Inc | FUSIONED RING COMPOUNDS CONTAINING NITROGEN AND USING THEMSELVES |
| WO2006068164A1 (en) | 2004-12-22 | 2006-06-29 | Ono Pharmaceutical Co., Ltd. | Tricyclic compound and use thereof |
| FR2901795A1 (en) * | 2006-05-30 | 2007-12-07 | Fourtillan Snc | DERIVATIVES OF PYRIMIDINO [1 ', 6'-1,2] PYRIDO [3,4-B] INDOLES AND THEIR USE IN THERAPEUTICS |
| FR2908768A1 (en) * | 2006-06-19 | 2008-05-23 | Fourtillan Snc | DERIVATIVES OF 3H, 11H-OXAZOLO (3 ', 4': 1,2) PYRIDO (3,4-b) INDOLE AND THEIR USE IN THERAPEUTICS |
| FR2912405A1 (en) * | 2007-02-08 | 2008-08-15 | Fourtillan Snc | DERIVATIVES OF IMIDAZO [1 ', 5': 1,6] PYRIDO [3,4-B] INDOLES AND THEIR USE IN THERAPEUTICS |
| JP2010540439A (en) * | 2007-09-20 | 2010-12-24 | ディー２イー，エルエルシー | Fluorine-containing derivatives of hydrogenated pyrido [4,3-b] indoles with neuroprotective and cognitive enhancing properties, processes for preparing and use |
| EP2225250A2 (en) * | 2007-11-30 | 2010-09-08 | Biota Scientific Management Pty Ltd | Bicyclic ppat inhibitors as antibacterial agents |
| DE102008025893B4 (en) * | 2008-05-26 | 2014-09-18 | Technische Universität Dresden | Process for the preparation of fatty acid amides with saturated, unsaturated or hydroxy fatty acids |
| BR112013021126A2 (en) | 2011-02-18 | 2019-09-24 | Medivation Technologies Inc | method for reducing blood pressure, method for increasing renal blood flow or decreasing sodium reabsorption, method for treating a disease, kit, compound and pharmaceutical composition |
| JP6107650B2 (en) | 2011-03-18 | 2017-04-05 | 小野薬品工業株式会社 | Tetrahydrocarboline derivative |
| KR101534523B1 (en) * | 2013-04-30 | 2015-07-09 | 경희대학교 산학협력단 | Cosmetic Composition for Skin Whitening Comprising 1,2,3,4-Tetrahydro-6-methoxy-1-oxo-beta-carboline |
| UY35590A (en) * | 2013-05-28 | 2014-11-28 | Astrazeneca Ab | NEW COMPOUNDS FOR CANCER TREATMENT |
| WO2020072675A1 (en) * | 2018-10-02 | 2020-04-09 | Northwestern University | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) |
| US10947253B2 (en) | 2019-08-05 | 2021-03-16 | Ankh Life Sciences Limited | Fused polycyclic dimers |
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| AR205452A1 (en) * | 1973-12-06 | 1976-05-07 | Endo Lab | METHOD TO PREPARE NEW TRANS-2, 3, 4, 4A, 5, 9B-HEXAHYDRO-5-PHENYL-1H-PYRID (4,3-B) INDOLES |
| FR2455044A1 (en) * | 1979-04-26 | 1980-11-21 | Synthelabo | PYRIDO-INDOLES AND THEIR APPLICATION IN THERAPEUTICS |
| JP2527319B2 (en) * | 1986-12-25 | 1996-08-21 | 川研ファインケミカル株式会社 | Method for producing 7-bromo-β-carboline derivative |
| EP0620222A3 (en) * | 1993-04-14 | 1995-04-12 | Lilly Co Eli | Tetrahydro-beta-carbolines. |
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-
1999
- 1999-07-23 FR FR9909576A patent/FR2796644B1/en not_active Expired - Fee Related
-
2000
- 2000-07-19 PL PL00341549A patent/PL341549A1/en not_active Application Discontinuation
- 2000-07-19 MX MXPA00007058A patent/MXPA00007058A/en unknown
- 2000-07-19 JP JP2000218942A patent/JP2001072679A/en active Pending
- 2000-07-20 CA CA002314473A patent/CA2314473A1/en not_active Abandoned
- 2000-07-21 NO NO20003764A patent/NO20003764L/en unknown
- 2000-07-21 AU AU48769/00A patent/AU762958B2/en not_active Ceased
- 2000-07-21 ZA ZA200003702A patent/ZA200003702B/en unknown
- 2000-07-21 CN CN00121615A patent/CN1282743A/en active Pending
- 2000-07-21 EP EP00402073A patent/EP1070716A1/en not_active Withdrawn
- 2000-07-21 NZ NZ505903A patent/NZ505903A/en unknown
- 2000-07-21 US US09/621,742 patent/US6350757B1/en not_active Expired - Fee Related
- 2000-07-21 HU HU0002843A patent/HUP0002843A3/en unknown
- 2000-07-21 EA EA200000700A patent/EA004140B1/en not_active IP Right Cessation
- 2000-07-24 KR KR1020000042401A patent/KR20010049859A/en not_active Application Discontinuation
- 2000-07-24 BR BR0003105-4A patent/BR0003105A/en not_active IP Right Cessation
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046175B (en) * | 2008-03-12 | 2015-08-12 | 细胞内治疗公司 | The heterocyclic fused gamma-carbolines solid replaced |
| US9260429B2 (en) | 2008-03-24 | 2016-02-16 | Medivation Technologies, Inc. | Pyrido[3,4-B]indoles and methods of use |
| US9469641B2 (en) | 2008-03-24 | 2016-10-18 | Medivation Technologies, Inc. | Pyrido[3,4-B]indoles and methods of use |
| CN102711467A (en) * | 2009-09-23 | 2012-10-03 | 梅迪维新技术公司 | Pyrido(3,4-b)indoles and methods of use |
| CN102724875A (en) * | 2009-09-23 | 2012-10-10 | 梅迪维新技术公司 | Pyrido[3,4-b]indoles and methods of use |
| CN102724875B (en) * | 2009-09-23 | 2015-05-27 | 梅迪维新技术公司 | Pyrido[3,4-b]indoles and methods of use |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1070716A1 (en) | 2001-01-24 |
| HUP0002843A2 (en) | 2001-04-28 |
| AU762958B2 (en) | 2003-07-10 |
| HUP0002843A3 (en) | 2001-07-30 |
| EA004140B1 (en) | 2004-02-26 |
| NO20003764L (en) | 2001-01-24 |
| HU0002843D0 (en) | 2000-09-28 |
| PL341549A1 (en) | 2001-01-29 |
| BR0003105A (en) | 2001-03-13 |
| ZA200003702B (en) | 2001-05-21 |
| KR20010049859A (en) | 2001-06-15 |
| MXPA00007058A (en) | 2002-04-24 |
| EA200000700A3 (en) | 2001-04-23 |
| NZ505903A (en) | 2001-08-31 |
| CA2314473A1 (en) | 2001-01-23 |
| FR2796644A1 (en) | 2001-01-26 |
| FR2796644B1 (en) | 2001-09-07 |
| EA200000700A2 (en) | 2001-02-26 |
| AU4876900A (en) | 2001-01-25 |
| NO20003764D0 (en) | 2000-07-21 |
| JP2001072679A (en) | 2001-03-21 |
| US6350757B1 (en) | 2002-02-26 |
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